This program project will apply molecular approaches to investigate the responses of human tumor cells to ionizing radiation. Radiobiologically well-characterized, low passage cell lines established from patients with squamous cell carcinomas of head and neck origin are categorized as displaying "resistant" or "sensitive" phenotypes to killing by ionizing radiation. The cells are then analyzed to determine differential gene expression (project #1), mechanisms of resistance related to oncogene expression (project #2), DNA damage and repair (project #3), and antisense vector and oligonucleotide mediated approaches to modulation of the resistant phenotype (project #4). We will test the hypothesis that the responses of tumor cells to ionizing radiation (sensitivity or resistance) are the result of differential gene expression. Using the techniques of 2-D protein gel electrophoresis and microsequencing, cDNA subtraction hybridization, and vector mediated gene transfer, we will identify genes association with the radiation resistant or radiation sensitive phenotype. Our analysis of the role of these genes in the radiation response of tumor cells will provide insight into the basic mechanisms of radiation killing and permit molecular strategies to improve the therapeutic ratio.